Laboratory Medicine Flashcards
van der waals
shifting electrons density in areas of a molecule or in a molecule as a whole results in the generation of transient positive or negative charges. these areas interact with transient areas of opposite charge on another molecule
hydrogen bond
hydrogen atoms bound to N or O become more positively polarized, allowing them to bond to more negatively polarized atoms such as O, N, or S
ionic
atoms with an excess of electrons (so neg charge) are attracted to atoms with a deficiency of electrons (pos charge)
covalent
two bonding atoms share electrons
Factors that affect interactions
- hydrophobicity
- hydrophilicity
- pka of AA near binding site
- conformation
- stereochemistry
induced fit
binding of the drug to the receptor causes conformational change and increased affinity
-drug binding improve quality of binding interaction but also alter the active of the receptor
active site
binding site of drugs on receptor
specificity
determined by factors of:
- drug and receptor structure
- chemical forces influencing drug-receptor interaction
- drug solubility in water and in the plasma membrane
- function of receptor in cellular environment
selectivity
the idea that drugs only interact with molecular target that causes desired therapeutic effects but not with molecular targets with cause unwanted effects
selectivity conferred by:
- cell-type specificity of receptor subtypes
- cell-type specificy of receptor-effector coupling
how does cell-type specificity of receptor subtypes effect selectivity
the more restricted the cell-type distribution of the receptor targeted by a particular drug , the more selecitve the drug is likely to by
how does cell-type specificity of receptor-effector coupling effect selectivity
the more receptor-effector coupling mechanisms differ among the various cell types that express a particular molecule target for a drug, the more selective the drug is likely to be
full agonists
bind to and activate targets to max extent
partial agonists
produce a submaximal response upon binding to their targets
inverse agonists
cause constitutively active targets to become inactive
competitive anatagonists
drugs that directly block the binding site of a physiological agonist
non-competitive antagonists
drugs that bind to other sites on the target molecule and thereby prevent the conformational change required for receptor activation (or inactivation)
Transmembrane linked to intracellular and G protein describe the general GPCR activiation
7 transmem regions with single polypep chain
- agonist to receptor
- alpha subunit exchanges GDP->GTP
- alpha GTP disassociates from betagamma and diffuses along inner leaflet of the plasma membrane to interact with a number of different effectors
- signals mediated by g proteins are terminated by hydrolysis of GTP->GDP
Some effectors of gPCR
- PLC cleaves PIPz to DAG (smooth m contraction) and IP3 (inc cytoplasmic ca)
- adenylyl cyclase activated cAMP
- ion channels
- proteins
Major G proteins and examples of their actions
- G-stim (Gs): activiates ca2 channels, acitivate adenylyl cyclase
- G-inhibit (Gi): activates K channels, inhibits adenylyl cyclase
- Go: inhibits ca channels
- Gq: activates phospholipase C
- G12/13: diverse ion transporter interactions
Transmembrane ion channels
- ligand gated
- voltage gated
- second messenger-regulated
transmembrane with enzymatic cytosolic domain
- single-mem spanning
- work by phosphorylating AA residues with changes structure of protein and thus activates it
- tyrosine kinases
drugs that do not fit the drug-receptor model
- osmotic diuretics
- antacids
occupancy theory
the idea that a response emanates from a receptor only when it is occupied by an appropriate ligand
spare receptor concept
when maximal response is chieved without 100% receptor occupancy; maximal effect is achieved at a lower dose of agonist than that required for receptor saturation (EC50>Kd)
mechanisms thought to be responsible for discrepancy between the drug-receptor binding curve and the dose-response curve
- receptor could remain activiated after agonsit departs allowing one agonsit molecule to activate several receptors
- cell signaling pathway could allow for significant amplifaction of relatively small signal and activation of only a few receptors could be sufficient to produce a maximal response
